Speaker 1: Hi everyone. Aaron here you are about to listen to
Speaker 1: a very exciting episode on immortality. And this episode is
Speaker 1: not just exciting because of the topic, but also because
Speaker 1: it was going to be our one hundredth regular season episode.
Speaker 1: But when things with monkeypox started to ramp up, we
Speaker 1: decided that we wanted to make sure that we got
Speaker 1: a monkey pox's episode out to you as quickly as possible,
Speaker 1: and that meant pushing back this immortality episode, which we
Speaker 1: had actually recorded before monkey pocks. So throughout this episode
Speaker 1: you may hear references to this being our one hundredth episode,
Speaker 1: even though it's actually episode one hundred and one, and
Speaker 1: we just wanted to explain why in advance. Okay, I
Speaker 1: think that about covers it, So let's get started introducing immortality.
Speaker 1: The life that you seek you never will find. When
Speaker 1: the gods created mankind death, they dispensed to mankind life
Speaker 1: they kept for themselves. But you, Gilgamesh, Let your belly
Speaker 1: be full, enjoy yourself always by day and by night.
Speaker 1: Make mary each day, dance and play day and night.
Speaker 1: Let your clothes be clean, Let your head be washed.
Speaker 1: May you bathe in water. Gaze on the child who
Speaker 1: holds your hand. Let your wife enjoy your repeated embrace.
Speaker 2: I still don't actually know the story of Gilgamesh.
Speaker 1: I still only know a little part of the story
Speaker 1: of Gilgamesh. So yes, that was from the epic of Gilgamesh,
Speaker 1: which is one of the oldest I think actually the
Speaker 1: considered the oldest like surviving document or text.
Speaker 2: Wow, that's amazing.
Speaker 1: Yeah, yeah, it's from a long time ago, like two
Speaker 1: thousand BCE something like that.
Speaker 2: Wow.
Speaker 1: Yeah. Hi, I'm Aaron Welsh.
Speaker 2: And I'm Aaron Allman Updike.
Speaker 1: And this is this podcast will kill you.
Speaker 2: And today we're not just like reading you the story
Speaker 2: of Gilgamesh.
Speaker 1: That's most of what you'll hear about Yogamesh.
Speaker 2: Today, we're doing something very different in honor of our
Speaker 2: one hundredth episode.
Speaker 1: One hundredth I mean it is. I can't believe it.
Speaker 2: I never would have thought we could make one hundred
Speaker 2: episodes of a podcast, Darin either.
Speaker 1: And Okay, here's the thing is that, like technically we
Speaker 1: surpassed one hundred a long time.
Speaker 2: That's true. I forgot about that with.
Speaker 1: Like all the COVID episodes and all the bonus one
Speaker 1: bonus episodes. Yeah, still, this is this is our like
Speaker 1: our title episode one hundred, Yeah, and I think in
Speaker 1: honor of that, as we slowly get around to talking
Speaker 1: about what we're going to be talking about today, we
Speaker 1: thought it would be fun to take the name of
Speaker 1: our podcast and change it up a bit, right, this
Speaker 1: podcast will kill you today.
Speaker 2: This podcast won't kill you. Yeah, it might make you
Speaker 2: live forever, probably not give you the secrets to eternal life.
Speaker 1: Today, we're going to be talking about immortality and aging.
Speaker 1: And it's definitely not going to be a comprehensive journey
Speaker 1: through the history of aging and how immortality could be achieved,
Speaker 1: but I think it's going to be a nice little taste.
Speaker 2: Yeah, And our structure is going to be a little
Speaker 2: different than usual because it's such an amorphist topic. Yeah.
Speaker 1: So I'm going to be starting out talking about the
Speaker 1: history of immortality and what that means in terms of evolution,
Speaker 1: and then what that means in terms of like human culture,
Speaker 1: and again it's just sort of like a brief, little
Speaker 1: jump through, yeah topic.
Speaker 2: And then I'm going to talk about I don't really
Speaker 2: know what erin maybe like where we stand in terms
Speaker 2: of like aging today or anti aging research or the
Speaker 2: quest for immortality, what we know about the biology of it.
Speaker 1: I don't know.
Speaker 2: It's going to be a little bit of a conversation.
Speaker 1: I think it's going to be really exciting and fun. Yeah,
Speaker 1: I'm just looking.
Speaker 2: Forward to us same same Well, speaking of like.
Speaker 1: Tastes of things. What time is it?
Speaker 2: Oh, quarantiny time still is quarantiny time.
Speaker 1: Still is always quarantiny time. What are we drinking this week?
Speaker 2: Well, of course we're drinking none other than the Elixir
Speaker 2: of Life.
Speaker 1: We are and in the Elixir of Life. It's a
Speaker 1: it's a fun little it's a fun little drink because
Speaker 1: we've got gin, we've got lemon juice, we've got blackberries,
Speaker 1: we've got simple syrup. And then to kind of like
Speaker 1: create the fun little magical I don't know aura around it,
Speaker 1: we've got butterfly pea flower extract, which was sent to
Speaker 1: us by a very generous listener, so thank you so much.
Speaker 1: It is such a cool looking drink.
Speaker 2: It's a nice I'm really excited about. I want to
Speaker 2: come visit you so that I can actually taste it.
Speaker 1: Okay, let's make that happen. Yeah, we will post the
Speaker 1: full recipe for the Elixir of Life as well. As
Speaker 1: the non alcoholic place Rita on our website This podcast
Speaker 1: will kill You dot Com, as well as on all
Speaker 1: of our social media channels.
Speaker 2: Our website This podcast will kill You dot Com. If
Speaker 2: you haven't been there yet, you should go and check
Speaker 2: it out. After one hundred episodes, try it. We have
Speaker 2: merch we have transcripts. We have links to our bookshop
Speaker 2: dot org affiliate account. We have links to our music bloodmobile.
Speaker 2: We have a good Reads list, we have all of
Speaker 2: our sources for all of our episodes. We have our Patreon.
Speaker 2: We have more than I could say in that single breath.
Speaker 1: Well, I think you did a great job. Thanks, loving
Speaker 1: all right, any other business?
Speaker 2: No, Aaron, please tell me, like I don't know, from
Speaker 2: Gilgamesh to now, how has humanity fared on our quest
Speaker 2: for immortality?
Speaker 1: Great questions there I will, I will do my very
Speaker 1: best right after this break. Like we said, this is
Speaker 1: definitely not our typical format. But then again, this is
Speaker 1: not our typical episode topic. So the focus of our
Speaker 1: episode today is immortality. But what does that mean? Not
Speaker 1: just like what are we going to cover, but the
Speaker 1: word or the concept itself is immortality, simply living forever,
Speaker 1: not aging, being invulnerable to any illness or injury. Does
Speaker 1: it mean that your name and life will be remembered
Speaker 1: hundreds of years from now, or that your genes will
Speaker 1: be carried on in your offspring and their offspring, and
Speaker 1: so on and so on down the line. There are
Speaker 1: many different ways that we can think of and have
Speaker 1: thought of immortality. And if your goal is to achieve immortality,
Speaker 1: which definition you choose has tremendous bearing on how you
Speaker 1: go about that, And that can also be said for
Speaker 1: this episode. So how will we consider immortality today? Really,
Speaker 1: we'll at least touch on the most common concepts in
Speaker 1: a general sense, but since we're a health and science podcast,
Speaker 1: most of what we'll talk about is immortality from a
Speaker 1: biological perspective. First by talking about not what immortality is
Speaker 1: and how we can achieve it, but what stops us
Speaker 1: from being immortal in the first place? Why do we die?
Speaker 1: Why do we decline as we get older? Are there
Speaker 1: any organisms that don't? What do we know or think
Speaker 1: about senescence, the decline or deterioration we experience as we
Speaker 1: age from an evolutionary perspective, And then all turn from
Speaker 1: that to talking about the age long quest for immortality,
Speaker 1: which has roots much much older than these startups in
Speaker 1: Silicon Valley that have been looking for modern elixirs of
Speaker 1: life that I know you're going to be talking a
Speaker 1: bit more about, Aaron Yeap. What patterns do we see
Speaker 1: in the different ways that people have approached immortality through history?
Speaker 1: And how has this past century and our ever growing
Speaker 1: understanding of biology changed the targets for immortality research. And
Speaker 1: then that's sort of where I'll hands it off to
Speaker 1: you Erin to tell us how close we are or
Speaker 1: probably aren't to achieving immortality and the nitty gritty of
Speaker 1: what people are working on. Okay, okay, all right, so
Speaker 1: let's get into it. Living things age, but they don't
Speaker 1: just experience the passage of time. They also change as
Speaker 1: time passes, first growing and developing, and then at a
Speaker 1: certain point that growth ceases and a new kind of
Speaker 1: change occurs, one where maybe things don't heal quite as
Speaker 1: fast as they used to, or those aches and pains
Speaker 1: get more frequent, and eventually recovery is no longer a possibility,
Speaker 1: with death being the ultimate end. And this is generally
Speaker 1: how it happens for every living thing. And sure, the
Speaker 1: amount of time that you spend in each life stage
Speaker 1: may be different, or how long you can expect to
Speaker 1: live will vary, but death and aging are essential parts
Speaker 1: of life, even for those supposedly immortal animals that you
Speaker 1: see like click bait headlines about like lobsters or certain
Speaker 1: jellyfish or bristle cone pines. But while senescence, the biological
Speaker 1: decline part of aging may not be as marked as
Speaker 1: in other creatures, those organisms are not truly immortal. They
Speaker 1: will die eventually because nothing living is immune to death.
Speaker 1: Why does this have to happen? Like, why can't we
Speaker 1: go on living forever? Well, let's think about it in
Speaker 1: the context of natural selection and evolutionary fitness.
Speaker 2: That's arh.
Speaker 1: Evolutionary fitness, for those who haven't heard the term before,
Speaker 1: is essentially an individual's reproductive success how many offspring they have.
Speaker 1: If an individual has no offspring, zero fitness. If they
Speaker 1: don't survive long enough to reproduce, fitness is also zero.
Speaker 1: But the individuals who do live long enough to reproduce
Speaker 1: and have a lot of offspring, those are the ones
Speaker 1: who are going to contribute the most to the next
Speaker 1: generation's gene pool. Traits that limit your ability to reproduce
Speaker 1: or survive through reproductive age. Those traits lower your fitness
Speaker 1: and make it less likely for those genes to be
Speaker 1: passed on to the next generation. And over time those
Speaker 1: traits those genes will become less and less common, maybe
Speaker 1: eventually disappearing. But traits that make you more likely to
Speaker 1: reproduce or survive through the end of reproductive age, those
Speaker 1: are the traits that are going to be selected for
Speaker 1: becoming more common. So we can think of tons of
Speaker 1: examples of this, right, like the size of a bird's beak,
Speaker 1: or the rate of development of a tadpole into a frog,
Speaker 1: or fur pattern or susceptibility to disease. But what's so
Speaker 1: crucial about this for this discussion is not the trait themselves,
Speaker 1: not these examples, but rather the time window when these
Speaker 1: traits matter most, and that is the critical period from
Speaker 1: basically prenatal development all the way through the end of
Speaker 1: when you are able to reproduce. That is when selection
Speaker 1: can act. With this in mind, what does it matter
Speaker 1: really in terms of natural selection if you live past
Speaker 1: reproductive age. It doesn't.
Speaker 2: It doesn't at all.
Speaker 1: It doesn't. Yeah, if there are genes that affect at
Speaker 1: least in part your longevity. How will natural selection act
Speaker 1: on them if they don't have any bearing on your
Speaker 1: reproductive fitness. It won't, It won't, I mean, And there
Speaker 1: are genes in humans that are associated with longevity, but
Speaker 1: it's likely that those play a role in maintenance or development,
Speaker 1: and they don't just switch on later in life exactly. Yeah.
Speaker 1: So essentially, in terms of natural select it doesn't really
Speaker 1: matter how long we live past the point when we're
Speaker 1: no longer reproductively viable. And this is of course like
Speaker 1: a big oversimplification, and for humans and other animals, there
Speaker 1: are some very interesting hypotheses about why we humans live
Speaker 1: long past the age we reproduce, mostly centering around grandparents,
Speaker 1: and I'd love to get into that one day with
Speaker 1: an episode on menopause. Oh.
Speaker 2: I we'll definitely do it on menopause because I love
Speaker 2: all of the evolutionary theories behind menopause and just like aging,
Speaker 2: and like the grandparents.
Speaker 1: Oh, I love the grandparent hypothesis. Oh it's so interesting.
Speaker 2: Yeah, I love it.
Speaker 1: But anyway, we humans are not unique in that we
Speaker 1: live past the age we reproduce, nor are we unique
Speaker 1: in the fact that our bodies and minds start to
Speaker 1: deteriorate as we get older. And even if life past
Speaker 1: reproduction is not part of natural selection, what makes us
Speaker 1: and other organisms age? Like? Why do we age? And
Speaker 1: we have been asking ourselves this question, probably since we
Speaker 1: were able to form thought, but it wasn't until Charles
Speaker 1: Darwin introduced the theory of evolution by natural selection in
Speaker 1: the mid nineteenth century that people had a scientific framework
Speaker 1: that they could use to try to answer this question.
Speaker 1: Since that time, many different hypotheses have been proposed, none
Speaker 1: of which seem to adequately explain sinessence for every living thing.
Speaker 1: And I'm going to briefly go through a few of
Speaker 1: the classical hypotheses of sinessence so that we can try
Speaker 1: to think about possible mechanisms that could explain why aging
Speaker 1: is universal. The first of these hypotheses was proposed in
Speaker 1: the eighteen nineties by the German evolutionary biologist August Weismann
Speaker 1: the so called germ soma theory, and so Weisman suggested
Speaker 1: that there were two types of cell lines in an organism,
Speaker 1: a germ line and a soma or body line, and
Speaker 1: the germ line is made up of the cells that
Speaker 1: are involved in reproduction and the soma line consists of
Speaker 1: the cells that make up the rest of the body.
Speaker 1: It's the sole duty of the soma cells to do
Speaker 1: whatever it takes to keep the germ line alive and reproducing.
Speaker 1: Beyond that, soma cells basically disposable, and the soma cell
Speaker 1: lineage will invariably die, while the germ cell lineage can
Speaker 1: be viewed as potentially immortal. Aging happens as the soma
Speaker 1: line gets beat up by the environment while protecting the
Speaker 1: germ line. And that's the hypothesis. Yeah, obviously it has
Speaker 1: many shortcomings, first of them being that it doesn't really
Speaker 1: explain why sinessence evolved, like why the soma is disposable,
Speaker 1: and it doesn't explain sinessence in single celled organisms. But
Speaker 1: it did introduce the idea that reproduction is first and
Speaker 1: foremost the priority, and many later researchers built upon this idea,
Speaker 1: such as the famous mathematician and eugenicist Ronald Fisher, who
Speaker 1: in the nineteen thirties proposed a mathematical model in which
Speaker 1: he laid out his thoughts that sinessence was the accumulation
Speaker 1: of harmful age specific traits. A couple of decades later,
Speaker 1: in the nineteen fifties, Peter Medowar, whose name you might
Speaker 1: remember from our organ transplantation episode. He wrote a now
Speaker 1: famous essay describing how the force of selection weakens as
Speaker 1: we get older and past our reproductive age. He wasn't
Speaker 1: entirely right either, For instance, his belief that animals in
Speaker 1: the wild don't get old they don't siness because they
Speaker 1: just get picked off by predators or succumb to starvation.
Speaker 1: They actually do siness, they actually do get older. But
Speaker 1: his essay did suggest a sort of mechanism for Sinessence,
Speaker 1: if there are genes that do exist that shorten our lifespan,
Speaker 1: they won't really be selected against if they only show
Speaker 1: their effects later in life, and so they will continue
Speaker 1: to appear and accumulate over generations. The quote mutation accumulation theory.
Speaker 2: That's I love. Sorry, I just really do love these hypotheses.
Speaker 1: I do too.
Speaker 2: I find it really fun.
Speaker 1: It was it was so interesting because I have never
Speaker 1: even though I said, humans have probably asked themselves this
Speaker 1: question forever, and I've probably asked myself this question too,
Speaker 1: but not in like a okay, but why what is
Speaker 1: the actual evolutionary mechanism behind it?
Speaker 2: I feel like I only ever thought about another hypothesis.
Speaker 2: I think you're probably going to talk about next in
Speaker 2: the context of the evolution of human health class that
Speaker 2: I ta' for. So that was like a very specific
Speaker 2: subset of time that I was thinking about it.
Speaker 1: Yeah, it is. It's so fun to think about. Okay,
Speaker 1: so there are there are a few more.
Speaker 2: Yeah.
Speaker 1: So. Years after Metowar's essay, George Williams added on to
Speaker 1: this by suggesting that in addition to these mutations appearing,
Speaker 1: it's also possible that those genes that are helpful early
Speaker 1: in life, like in development and during reproduction, could also
Speaker 1: be bad or have negative effects later in life. Like,
Speaker 1: for instance, let's think about cell growth. If your cells
Speaker 1: grow super fast, that's potentially great when you're developing right,
Speaker 1: you get larger faster and can be independent faster. But
Speaker 1: later on that could mean uncontrolled cell growth aka cancer.
Speaker 2: Yep.
Speaker 1: And this is something that's called antagonistic pliotropy.
Speaker 2: It's one of my favorite concepts and I love it.
Speaker 1: It's so it's I mean, and it like the thing
Speaker 1: they all make sense, And the thing that I like
Speaker 1: too about them is that none of them are really
Speaker 1: mutually exclusive.
Speaker 2: Exactly like you have, you can easily we have mutations
Speaker 2: that accumulate as well as have genes that are beneficial
Speaker 2: early in life and maybe have a detriment later in life.
Speaker 2: So like these mutation, accumulation, antagonistic piotropy, these hypotheses really
Speaker 2: do work together to explain aging in a way that
Speaker 2: I think is just fascinating.
Speaker 1: Yep, yeah, exactly. And also what really helped things along
Speaker 1: in this in this field was when in nineteen sixty
Speaker 1: six William Hamilton combined some of these existing ideas on
Speaker 1: the evolution of aging into a mathematical model, which, like,
Speaker 1: maybe that doesn't sound very exciting, but it really is.
Speaker 1: It was, and it's still today is super impactful because
Speaker 1: it laid out a framework for why aging happens, and
Speaker 1: it also showed that the strength of selection on traits
Speaker 1: that keep you alive it becomes weaker over time in
Speaker 1: anything that ages and doesn't reproduce via fission. Yeah. Really,
Speaker 1: Also what it did was create a math model for
Speaker 1: people to be able to to test ideas about aging.
Speaker 1: The last of the classical hypotheses of sinessence I'm going
Speaker 1: to talk about is the quote disposable soma theory. Proposed
Speaker 1: by Thomas Kirkwood in nineteen seventy seven, which says that
Speaker 1: over time and organism cells accumulate harmful genetic mutations. Mutations
Speaker 1: in your DNA happen randomly all the time because of
Speaker 1: environmental factors or mistakes in DNA replication, and it gets
Speaker 1: increasingly costly to repair the damage from these mutations, and
Speaker 1: at a certain point, the benefit of repairing the damage
Speaker 1: is outweighed by the cost repair and maintenance is always
Speaker 1: going to favor the germline. Okay, so these are just
Speaker 1: a few of the most impactful hypotheses to explain why
Speaker 1: sinessence evolved, but there are certainly others, and no single
Speaker 1: hypothesis at this point seems to be able to explain
Speaker 1: aging for all organisms. There's no unifying hypothesis, probably because
Speaker 1: like there's tremendous diversity in life, no is there.
Speaker 2: Really are I mean that like a bristle combe pine
Speaker 2: is not the same thing as a plenariat.
Speaker 1: It might not be, and even some of the fundamental
Speaker 1: assumptions about aging have been challenged. It's an extraordinarily complicated
Speaker 1: thing to study. You have to capture both how different
Speaker 1: environments and different genes impact aging. You have to consider
Speaker 1: ecological factors, determine whether aging in the lab is different
Speaker 1: or the same as aging in the wild, evaluate whether
Speaker 1: closely related species age more similarly than distantly related ones.
Speaker 1: And the biggest thing in my eyes is that we've
Speaker 1: really only begun looking at this within the past one
Speaker 1: hundred and thirty years or so, which is shorter than
Speaker 1: the average lifespan of some organs. That could give us
Speaker 1: really valuable insight into longevity.
Speaker 2: Good point, So, like, how do you how do.
Speaker 1: You create a data set? Yeah, for giant tortoise?
Speaker 2: Right, well, even studying human aging, like we live a
Speaker 2: really long time, right, and.
Speaker 1: There have been really cool like census records and especially
Speaker 1: in certain countries or certain regions that keep really good
Speaker 1: track of like people through time, but we still don't
Speaker 1: have all the bits of information there, right.
Speaker 2: Yeah.
Speaker 1: So it's it's in a way we've been thinking about
Speaker 1: it for a long time, but it seems like we're
Speaker 1: definitely in the infancy of having data to be able
Speaker 1: to test these hypotheses.
Speaker 2: Aaron, you just summed up my whole section.
Speaker 1: It's it was it was really interesting to read through
Speaker 1: this also because I don't think I realized just how
Speaker 1: huge of a field of study this, And I guess
Speaker 1: I should have because there are like, you know, entire
Speaker 1: journals and entire textbooks at entire companies and everything, but
Speaker 1: like it is, it is really hard to do it justice. Yeah, yeah,
Speaker 1: so yeah, So I just kind of wanted to like
Speaker 1: wander through some of these ideas and kind of fell
Speaker 1: and build a baseline for thinking about aging in an
Speaker 1: evolutionary context, especially when it comes to like natural selection
Speaker 1: and wouldn't it be great if we lived forever but
Speaker 1: we don't really need to, yeah, in terms of our DNA.
Speaker 2: Getting passed on, Yeah, exactly.
Speaker 1: Yeah, And I also thought it was important to think
Speaker 1: about these things like why we age before we start
Speaker 1: exploring some of the ways that we've tried and continue
Speaker 1: to try to stop or slow that process. So, if
Speaker 1: they're there is anything that humans are good at, it's
Speaker 1: searching for the key to immortality. We're really good at
Speaker 1: searching for it, but we are terrible at finding it. Yeah,
Speaker 1: because we've not found it. Yeah, spoilers, we don't have it. Spoilers,
Speaker 1: we don't have it. We may not have it ever.
Speaker 1: Immortality narratives are central to every culture and religion, like
Speaker 1: the Epic of Gilgamesh, the oldest known written document. So
Speaker 1: the reason that I included Gilgamesh in the beginning, I'm
Speaker 1: like now calling back to it is that a big
Speaker 1: part of the story is about the quest for immortality.
Speaker 1: So King Gilgamesh's best friend dies and in response, Gilgamesh
Speaker 1: vows to find eternal life. Spoilers he does not. And
Speaker 1: I'm sure between the two of us we can think
Speaker 1: of dozens and dozens more books or movies or poems
Speaker 1: or songs about the search for eternal life. But it's
Speaker 1: not just like one of my favorite books growing up.
Speaker 1: Let's talk Everlasting and for a long time you have
Speaker 1: you read talk ever Lasting?
Speaker 2: Rush. I didn't even know it was a book. I
Speaker 2: thought it was a movie, but I've never seen.
Speaker 1: It, okay, or read it. Basically, it's about this family
Speaker 1: that is trying to find like a home. They're like homesteading,
Speaker 1: and they stumble across this water. They all drink from it,
Speaker 1: including the horse, I think, and it happens to be
Speaker 1: like an immortality.
Speaker 2: Spring.
Speaker 1: And then then there's like a girl who stumbles across
Speaker 1: his family and then she's like, do I drink it?
Speaker 1: Do I? Not drink it, blah blah blah, And as
Speaker 1: a kid, I was like, drink it, obviously.
Speaker 2: Drink ever, don't drink it.
Speaker 1: And yeah, anyway, but it's a really interesting contemplation about
Speaker 1: immortality and and life. I loved it. And that's just
Speaker 1: one of like hundreds, dozens, thousands, an unbelievable number. But
Speaker 1: it's not just in these fictional stories that people have
Speaker 1: been on the hunt for a way to live forever.
Speaker 1: The quest for immortality is a very real thing that
Speaker 1: takes many different forms, and I want to talk a
Speaker 1: bit about these forms before focusing on a couple that
Speaker 1: are more in line with this episode. While researching for
Speaker 1: this episode, I came across a book titled Immortality, The
Speaker 1: Quest to Live Forever and How It Drives Civilization. And
Speaker 1: in this book, the author philosopher Stephen Cave, groups the
Speaker 1: search for immortality into four different themes. The first two
Speaker 1: deal with the physical side of things. First, there's living forever,
Speaker 1: you as an individual, stopping aging or aging but not dying,
Speaker 1: living indefinitely. And then there's resurrection, being brought back to
Speaker 1: life after death, think Jesus. Third is the soul, the
Speaker 1: idea that a part of you, but not the physical
Speaker 1: you lives on after you die. And finally, there's legacy,
Speaker 1: which can mean living on through memories or fame, as
Speaker 1: in your only truly dead when your name is no
Speaker 1: longer said Coco, or also offspring the idea that your
Speaker 1: genes achieve immortality by being passed on. And I wanted
Speaker 1: to explore some of the ways we've sought to achieve
Speaker 1: immortality throughout human history, focusing on those that fall into
Speaker 1: the first two of these themes, staying alive and resurrection,
Speaker 1: because in terms of targets for biological research into immortality,
Speaker 1: all of those projects can be lumped into those themes. Yeah,
Speaker 1: And after going through some of these adventures and immortality,
Speaker 1: I want to end by reflecting on what these stories
Speaker 1: tell us about human nature. Here. Humans may be unique
Speaker 1: in our ability to recognize our own mortality that one day,
Speaker 1: each and every one of us will die, and the
Speaker 1: knowledge of our own inevitable death, Yet the simultaneous inability
Speaker 1: to actually imagine what it will be like has driven
Speaker 1: us to find any way around it, either by delaying it,
Speaker 1: undoing it, or preventing it entirely. In ancient Egypt, there
Speaker 1: was an entire industry devoted to preserving the body after
Speaker 1: death so it could be magically revived, and of course,
Speaker 1: pyramids and other monuments were built as a testament to
Speaker 1: the person's life immortality through legacy. Ancient papyri describe not
Speaker 1: just preparation for the afterlife or resurrection, but also ointments
Speaker 1: and elixirs that were meant to extend life and slow aging.
Speaker 1: The search for an elixir of life or a fountain
Speaker 1: of youth is similarly old. There are countless stories of
Speaker 1: emperors and kings searching in vain for a way to
Speaker 1: escape death, like the first Emperor of China, who lived
Speaker 1: around the two hundreds BCE. He became obsessed with the
Speaker 1: idea of living forever and searched high and low for
Speaker 1: someone who could reveal the secret to him. He did
Speaker 1: find someone, probably one of the oldest known swindlers, who
Speaker 1: promised it all but delivered nothing and just ran away
Speaker 1: with his reward. Of course, ultimately the emperor died young,
Speaker 1: only forty nine, likely from either arsenic or lead or
Speaker 1: mercury poisoning, all of which were likely ingredients in his
Speaker 1: daily life. Extending vitamins.
Speaker 2: Oh gosh, that's just such a Bomber.
Speaker 1: I know, but he did achieve immortality. And what I mean,
Speaker 1: we're still talking about him. We are through his through legacy.
Speaker 1: He the terra Cotta Army. Have you heard of the Terracota? Yeah, yep,
Speaker 1: that's him.
Speaker 2: That's him. Huh, all right.
Speaker 1: The elixir of life wasn't always viewed as just a
Speaker 1: potion or something you ingest. At various points, it was
Speaker 1: thought to be a plant, or a series of exercises,
Speaker 1: or a special object like the Philosopher's stone, which was
Speaker 1: one of the mythical substances famous in alchemy. Alchemy was
Speaker 1: a kind of prescience practiced by philosophers and early chemists,
Speaker 1: the goal of which was to transform one metal into another,
Speaker 1: typically gold, and to find the elixir of immortality or
Speaker 1: a cure all for any disease. It was practiced all
Speaker 1: over the world from ancient times all the way up
Speaker 1: through the eighteenth century, when it declined after the rise
Speaker 1: of more rigorous scientific thinking, although it might be more
Speaker 1: accurate to say that alchemy didn't decline, but rather it
Speaker 1: was repackaged primarily into the field of chemistry. Nor did
Speaker 1: people grow tired of looking for the elae of immortality. Instead,
Speaker 1: the development of each new field or new scientific discovery
Speaker 1: was applied to that quest, For instance, electricity. So if
Speaker 1: you think back to our electricity episode, you may remember
Speaker 1: me telling the story of Galvani and his metal wires
Speaker 1: and the frog's legs jumping. So his nephew took a
Speaker 1: page out of his book and held public demonstrations where
Speaker 1: he reanimated corpses of freshly hanged murderers.
Speaker 2: Oh my, okay, yeah.
Speaker 1: And his demonstrations may have been the inspiration for Mary
Speaker 1: Shelley's Frankenstein.
Speaker 2: Oh my goodness.
Speaker 1: I know connections, and this pattern continues to be repeated.
Speaker 1: In the mid twentieth century, advancements in cellular technology allowed
Speaker 1: researchers to use previously frozen sperm for insemination, resulting in
Speaker 1: three pregnancies, which was revolutionary and that soon turned into
Speaker 1: whole body freezing plans. As we've learned more about genes
Speaker 1: linked to aging thanks to genomic sequencing technologies, those inevitably
Speaker 1: became our targets for modern day immortality projects. And the
Speaker 1: amazing thing in my eyes is that despite humanity's continuous
Speaker 1: and innumerable attempts to achieve immortality, over thousands and thousands
Speaker 1: of years, we have not been remotely successful, and we
Speaker 1: probably never will be. Maybe it'll change my mind.
Speaker 2: Yeah, we'll see erin.
Speaker 1: Over the past couple hundred years or so, the average
Speaker 1: age a person can expect to reach has been greatly extended,
Speaker 1: largely due to vaccines, antibiotics, and many other small things,
Speaker 1: especially a better understanding of disease overall. But this has
Speaker 1: not been an extension of our inherent life span. Humans
Speaker 1: have been able to live to eighty years old ninety
Speaker 1: years old for thousands of years, but were prevented from
Speaker 1: commonly achieving old age because of extrinsic factors like insert
Speaker 1: any vaccine preventable disease here.
Speaker 2: We're also taking like mercury and arsenic as a as
Speaker 2: a vitamin, just like that too.
Speaker 1: But from what I've read, there's not a single anti
Speaker 1: aging serum, pill, potion, whatever that has been shown to
Speaker 1: actually slow aging or reverse or stop it. There is
Speaker 1: some evidence that diet and exercise may play a role.
Speaker 1: Longevity and aging are both such incredibly multifaceted processes that
Speaker 1: are nearly impossible to predict, and I'm not saying at
Speaker 1: all that I don't think this research should be done.
Speaker 1: Some of these projects have uncovered knowledge that has had
Speaker 1: huge implications, who are improving quality of life and treating
Speaker 1: diseases that primarily manifest later in life. I guess I'm
Speaker 1: just expressing my skepticism that a meaningful extension of both
Speaker 1: lifespan and quality of life alongside that will be achieved
Speaker 1: in the near or even kind of near future. The
Speaker 1: section definitely came out differently than I had planned when
Speaker 1: I started it. I thought I'd take us through the
Speaker 1: history of the search for the elixir of life or
Speaker 1: the beginnings of cryonics, and those stories are fascinating and
Speaker 1: worth telling. But I think that overwhelmingly while doing the
Speaker 1: research for this part, and while going through it just now,
Speaker 1: I think that what sticks out to me most is
Speaker 1: how so many things have not changed. We will continue
Speaker 1: to keep looking for ways to live forever, to upload
Speaker 1: our brains or slow our aging, to reanimate form and bodies,
Speaker 1: or download our memories into a cloned body, and if
Speaker 1: any of those technologies are successful, you can also be
Speaker 1: sure that the select few, the richest, and most powerful
Speaker 1: will be the only ones to benefit from them, which
Speaker 1: is also how it has been throughout history. But would
Speaker 1: it truly be a benefit to live forever? Would it
Speaker 1: be something you want? I've talked about a few stories
Speaker 1: about people who have searched for a way to live forever.
Speaker 1: Now let's think of some where they achieved immortality. How
Speaker 1: did those stories end?
Speaker 2: Never well?
Speaker 1: Never well? Almost universally, they end in profound loneliness, sadness,
Speaker 1: and regret. Not at first maybe, but over time, as
Speaker 1: their mortal friends and family grow older and die, as
Speaker 1: days pass and time becomes meaningless. Granted, all of those
Speaker 1: stories have been imagined by mortal humans. These endings are
Speaker 1: just consolation for not being able to live forever. But
Speaker 1: I don't know. Personally, I don't think so. I think
Speaker 1: too often we decide we want to live forever without
Speaker 1: considering what that could truly look like. I want to
Speaker 1: end this section with a quote by Stephen Cave that
Speaker 1: I think puts it nicely. Quote The deep problem is this,
Speaker 1: The value of a thing is related to its scarcity.
Speaker 1: People conscious of their mortality value their time and aim
Speaker 1: to spend it wisely because they know their days are numbered.
Speaker 1: But if our days were not numbered, this incentive would disappear.
Speaker 1: Given infinity, time would lose its worth, and once time
Speaker 1: is worthless it becomes impossible to make rational decisions about
Speaker 1: how to spend it. The consequences of this for an
Speaker 1: individual would be bad enough. For a civilization of such ditherers,
Speaker 1: it would be disastrous.
Speaker 2: Yeah.
Speaker 1: Yeah, And with that, Aaron, oh gosh, I'll turn it
Speaker 1: over to you to tell me how close we are
Speaker 1: to such consequences.
Speaker 2: Oh my goodness, Arin, this episode turned out so different
Speaker 2: than we expected. I'm going to need a break, okay, Yeah,
Speaker 2: and then I'll dive in to what's happening today. So
Speaker 2: when I first started trying to research for this episode,
Speaker 2: I had a really hard time because I wasn't sure
Speaker 2: how to really approach this question. And I actually wasn't
Speaker 2: sure what my question was. I normally do the biology
Speaker 2: sect of whatever disease or thing we're talking about, and
Speaker 2: then I talk about the current status. Where do we
Speaker 2: stand today? So what was my question for immortality? Is it?
Speaker 2: How close are we to immortality? Is it? Are we
Speaker 2: still pursuing this quest? Which spoilers you already told us
Speaker 2: And the answer is yes, we still are. Oh was
Speaker 2: the question have we learned anything from these thousands of
Speaker 2: years of futility so far? I don't know what question
Speaker 2: I'm answering out of those. But I did a lot
Speaker 2: of reading, and I read a lot about the various
Speaker 2: you know, Silicon Valley startups that exist, the number of companies,
Speaker 2: the number of billionaires and millionaires, and the amount of
Speaker 2: dollars that are going in to try to solve this
Speaker 2: quote problem of aging or the problem of death.
Speaker 1: It kills me, the problem of aging, or it's really
Speaker 1: really interesting, and I think I got a little.
Speaker 2: Bit overwhelmed and also maybe a little cynical by the
Speaker 2: end of it.
Speaker 1: Oh, for sure, I got cynical by the end of
Speaker 1: the day.
Speaker 2: Yeah. But it's not to say, like what you said, Erin,
Speaker 2: It's not that what any of these researchers are doing
Speaker 2: is unimpressive or unimportant. It's just that we remain in
Speaker 2: the very early stages of this research. So let's kind
Speaker 2: of go through the way that I at least tried
Speaker 2: to frame thinking about this. If we're talking about immortality,
Speaker 2: like you said Erin at the top, then we're kind
Speaker 2: of talking about the idea of anti aging, or we're
Speaker 2: talking about increasing our lifespan. And if we're talking about
Speaker 2: halting aging to the point of halting death, then for me,
Speaker 2: the way to get there, logically is to answer a
Speaker 2: series of four different questions. The first question you kind
Speaker 2: of answered, Aaron, and that is why do we age?
Speaker 2: I think that you provided a lot of evolutionary perspective
Speaker 2: on the idea of why we as humans and we
Speaker 2: as living organisms on the planet Earth age evolutionarily, but
Speaker 2: we still don't fully necessarily know. We at least have
Speaker 2: a lot of hypotheses. But a very closely related question
Speaker 2: to why do we age is how do we age?
Speaker 2: Like fundamentally, what governs the process of how our selves siness?
Speaker 2: And how is this process related to those evolutionary reasons
Speaker 2: of why we age? Because if we could answer those
Speaker 2: two questions really well, then we could ask the next question,
Speaker 2: must we age? Are those processes, like we said, from
Speaker 2: an evolutionary perspective, necessary for life? And are they immutable?
Speaker 2: And if the answer to that question is no, they're
Speaker 2: not immutable. And if we can figure that out by
Speaker 2: virtue of figuring out the answers to the first two questions,
Speaker 2: then we can ask the final question, if we don't
Speaker 2: have to age, do we have to die? So, at
Speaker 2: least to me, those seem like the four fundamental questions
Speaker 2: that have to be answered if we have any hope
Speaker 2: of answering this riddle of immortality. And suffice to say,
Speaker 2: those four questions are massive, and I think the biggest
Speaker 2: issue for me in talking specifically about immortality is the
Speaker 2: leap between those last two questions, must we age and
Speaker 2: must we die? Right? Because while there are in nature
Speaker 2: and in the laboratory many many examples be they plant
Speaker 2: or worm or lobster that live a very long time
Speaker 2: that seem to be immortal, nothing is invincible, right, right.
Speaker 2: If you take one of these invincible planarians out of
Speaker 2: their worm juices, they're going to die. They're not invincible.
Speaker 2: And so that's I think one of the biggest issues
Speaker 2: I see with even just entertaining this idea of true immortality.
Speaker 1: Oh yeah, right, immortality is not invincibility exactly.
Speaker 2: Yeah, okay, But so is that what people are working on.
Speaker 2: Are people working on immortality or are people really working
Speaker 2: on the first few questions but selling it packaging it
Speaker 2: as the idea of immortality. Maybe that's more accurate. So
Speaker 2: what do we actually know about these first couple of questions,
Speaker 2: especially how we age and must we age? There has
Speaker 2: been like you said, Aaron, without a doubt huge increases
Speaker 2: in the estimated life expectancy for humans globally, and there
Speaker 2: is a lot of variation in estimated life expectancy between countries,
Speaker 2: between genders, et cetera. And most of that increase is,
Speaker 2: like you mentioned, credited to early life advancements, things like antibiotics, vaccines. Basically,
Speaker 2: we know for sure that we've had huge reductions in
Speaker 2: early life mortality because of scientific and biomedical achievements over
Speaker 2: the last fifty twoe hundred years. However, there has also
Speaker 2: been a decline in late life mortality. So the fraction
Speaker 2: of each birth cohort that reaches old age has been
Speaker 2: increasing year after year, or at least it had been
Speaker 2: until about the nineteen eighties, and since then it's actually
Speaker 2: been very stagnant despite increasing overall life expectancy, but the
Speaker 2: maximum reported age at death has plateaued. You may have
Speaker 2: heard of Jean Calmeat, who was a French woman who
Speaker 2: died in nineteen ninety seven at the ripe age of
Speaker 2: one hundred, twenty two years and five months. She still
Speaker 2: holds the verified longevity record by a lot, by a
Speaker 2: couple of years. And while there are over five hundred
Speaker 2: thousand centenarians alive worldwide, at least that's what the UN
Speaker 2: estimated in twenty twenty wow, five hundred thousand people over
Speaker 2: one hundred. That number is twenty times higher than fifty
Speaker 2: years prior. But the average age at death for these
Speaker 2: centenarians has not increased since nineteen sixty eight. So there
Speaker 2: is a lot of research and mathematical modeling like you
Speaker 2: mentioned erin as far back as the eighteen hundreds, that
Speaker 2: really suggest that there may be a true upper limit
Speaker 2: to the human life span. And while this idea is
Speaker 2: still a little bit controversial, there are people who don't
Speaker 2: like to agree with the idea that there is a
Speaker 2: limit to human life expectancy. A lot of studies that
Speaker 2: have used various methods and are to varying degrees controversial,
Speaker 2: have converged around this idea that perhaps between one hundred
Speaker 2: and twenty and one hundred and fifty years might be
Speaker 2: the maximum human lifespan that one could expect. So could
Speaker 2: we even live forever? It seems highly unlikely. Yeah, But
Speaker 2: there is another piece to this puzzle besides actual lifespan is,
Speaker 2: like you mentioned Aaron, quality of life. This is often
Speaker 2: called health span. So if life span is the length
Speaker 2: of your life. Health Span is often defined as the
Speaker 2: period of your life that is free from disease. I
Speaker 2: personally will take slight issue with this definition, because health
Speaker 2: is of course a lot more than merely the absence
Speaker 2: of disease, but this is generally how health span is defined,
Speaker 2: so we'll go with it for the purposes of this episode. Okay,
Speaker 2: And if we look worldwide, despite how much lifespan has increased,
Speaker 2: chronic diseases are the leading cause of morbidity and mortality worldwide,
Speaker 2: and many of these cardiovascular disease, cancer, dementia. These are
Speaker 2: often considered diseases of aging, and an estimated fifty eight
Speaker 2: percent of chronic disease related mortality happens in people over
Speaker 2: age seventy. So if we look at the discrepancy between
Speaker 2: health span and lifespan, there's an estimated gap right now
Speaker 2: in the world of nine years. So there's a nine
Speaker 2: year gap where you are still alive, but you are
Speaker 2: no longer quote free from disease. And a lot of
Speaker 2: the field of what is called gerontology research isn't truly
Speaker 2: focused on the idea of immortality, at least not overtly
Speaker 2: or in a lot of cases, they're not even focused
Speaker 2: on the idea of increasing our lifespan, but rather they're
Speaker 2: focused on increasing health span. So they talk instead about
Speaker 2: the idea of compressing our morbidity to the end of life,
Speaker 2: such that we live healthier lives for longer and can
Speaker 2: either avoid or prolong the onset of these various age
Speaker 2: related diseases. And this I think sits as both a
Speaker 2: more palatable goal. For sure, I would agree with that,
Speaker 2: but I also think that it's closer to what seems
Speaker 2: maybe yes, although I do stress that we're not there yet.
Speaker 1: It's it's so interesting because I think that, like, given
Speaker 1: the past one hundred and fifty years of scientific research,
Speaker 1: we tend to view things as science will always progress
Speaker 1: at an increasing rate. Yeah, right, like we make bigger
Speaker 1: leaps and bounds in our understanding and in our technology
Speaker 1: and so on, and it doesn't. That's not necessarily the case,
Speaker 1: I think with every field.
Speaker 2: Yeah, it is really really interesting to read a lot
Speaker 2: of this research and then also read the media reports
Speaker 2: about this research or about the companies that are funding this.
Speaker 1: Research, I bet, because.
Speaker 2: It's very different, right.
Speaker 1: Yeah, This is where reading between the lines of popular
Speaker 1: news articles is tricky. It's tricky, and where there's like
Speaker 1: have a heavy dose of skepticism and go to the
Speaker 1: original text.
Speaker 2: Yeah, definitely, But there are I will say a lot
Speaker 2: of researchers out there that are trying to really get
Speaker 2: into the nitty gritty of answering those first couple of
Speaker 2: questions that I posed, How and why do we age?
Speaker 2: And can we alter this process? So while we don't
Speaker 2: have a single answer, I will link to a couple
Speaker 2: of different papers that go into a lot more detail
Speaker 2: on these mechanisms. But we can define, based on what
Speaker 2: we know so far, about nine different flavors or nine
Speaker 2: different targets that are related to aging and potentially modifiable
Speaker 2: at least in cell culture and or in animal models,
Speaker 2: or maybe just theoretically modifiable. So I'll mention all of these,
Speaker 2: but spoiler alert. Reading some of the papers that go
Speaker 2: into detail on this, I had a very difficult time
Speaker 2: following through. But let's at least look at what we
Speaker 2: know about aging, because it turns out we know a
Speaker 2: lot more than you might think. So when we look
Speaker 2: at the mechanisms of aging, one of them Aaron you
Speaker 2: mentioned already, and that is damage to our DNA be
Speaker 2: that nuclear DNA or mitochondrial DNA. Basically, over time, insults
Speaker 2: to our bodies result in the inability of our bodies
Speaker 2: to properly repair damage to our DNA the way that
Speaker 2: it is supposed to. And there are a lot of
Speaker 2: different potential genes involved in this and specific mechanisms that
Speaker 2: researchers have altered in flies or in worms, or just
Speaker 2: in cells. But essentially this genomic instability does play a
Speaker 2: really big part in the process of aging. So if
Speaker 2: there was a way to make our DNA more easily
Speaker 2: able to repair itself, that could then delay that process
Speaker 2: of aging, and we know delay a lot of the
Speaker 2: age related diseases that are related to this, like cancers,
Speaker 2: like maybe heart disease. There's also telomere damage telomere's I
Speaker 2: think we talked about in our HPV episode. Was that right?
Speaker 1: You talked about it in some episode, but can you
Speaker 1: do a refresher?
Speaker 2: Of course, I'd love to so. Telomere's got a lot
Speaker 2: of press in aging a while back. But basically, they
Speaker 2: are the end caps of our DNA. They are these
Speaker 2: strings of repeat DNA that sit at the ends of
Speaker 2: our chromosomes and in a lot of cases, they don't
Speaker 2: get completely copied over when our cells divide, so over time,
Speaker 2: telomeres can become shortened, and this process of telomere shortening
Speaker 2: or telomere exhaustion then leads to a decline in the
Speaker 2: regenerative capacity of tissues and therefore accelerated aging. So in
Speaker 2: mice models and in other animal studies, telomere length has
Speaker 2: been shown to be associated with lifespan in humans. It's
Speaker 2: not quite that simple, but this is at least another
Speaker 2: potential target.
Speaker 1: What do you mean, it's not quite that simple.
Speaker 2: It's not like the length of your telomeres determines how
Speaker 2: long you're going to live. It's not a one to
Speaker 2: one association. So just adding on to our telomeres doesn't
Speaker 2: necessarily mean that we're going to increase our lifespan or
Speaker 2: our health span, because this is one of nine processes
Speaker 2: related to the aging process, nine that we know of
Speaker 2: so far. Okay, there's more lots and lots of research
Speaker 2: right now, especially by some of these big biotech companies
Speaker 2: into epigenetic modifications. Epigenetics we've only ever briefly mentioned, but
Speaker 2: I actually think I talked a bit about it in
Speaker 2: our full late episode. It's kind of fun.
Speaker 1: I was a thinking that, yeah, yeah.
Speaker 2: But basically, epigenetics are changes to DNA patterns that are
Speaker 2: not within the DNA itself, so not within a gene.
Speaker 2: But it's changes to things like methyl groups that are
Speaker 2: attached to our DNA. It's changes to things like histones,
Speaker 2: which are like the proteins that are DNA wraps itself around.
Speaker 2: It can be changes to how our DNA is stored.
Speaker 2: Any of these changes are considered part of epigenetics, and
Speaker 2: changes in a number of different things from methylation to
Speaker 2: histone proteins have been shown to be associated with aging.
Speaker 2: There is a family of enzymes called sirtuins I think
Speaker 2: that's how you pronounce it, that are involved in DNA
Speaker 2: methylation and got a lot of press because in yeast
Speaker 2: and in worms, when these enzymes are manipulated, then you
Speaker 2: can increase lifespan by significant in a worm. Again in humans,
Speaker 2: we don't have any data to show that as of yet,
Speaker 2: but that's at least the idea that epigenetics likely plays
Speaker 2: a big role in the process of aging. So if
Speaker 2: this is something that we could target, we could maybe
Speaker 2: affect it. Yet another target would be proteastasis, so Basically,
Speaker 2: our cells are both DNA and proteins, right, So as
Speaker 2: we age, our cells become less able to maintain proteins
Speaker 2: in the correct stable configurations and correct functionality. If you
Speaker 2: think of something like Alzheimer's disease, this is largely a
Speaker 2: disease of protein misfolding. So there are a lot of
Speaker 2: studies in cells in yeast, and I think at least
Speaker 2: some in worms and flies that if you mess with
Speaker 2: some of the genes related to protein stability, then you
Speaker 2: can precipitate aging make them age faster. So that suggests
Speaker 2: that these systems are directly involved in the process of aging,
Speaker 2: and thus if they could be manipulated in the opposite way,
Speaker 2: could perhaps promote longevity or reverse aging.
Speaker 1: Reverse aging. Interesting, say, yeah.
Speaker 2: Yeah, there's more. I'm only on number four of nine.
Speaker 2: I don't have goodness as much detail on all of them.
Speaker 2: Let me tell you. There's also the idea, and I
Speaker 2: think this one has gotten probably the most press very recently,
Speaker 2: or at least maybe just the most press of the
Speaker 2: press that I read. But it's this idea of as
Speaker 2: we age, we have a deregulated ability to do nutrient sensing. Basically,
Speaker 2: our bodies are not able to tell as we age
Speaker 2: if we have an abundance of food or if we
Speaker 2: have not enough food. And this goes along with a
Speaker 2: lot of data in mice and in some primates of
Speaker 2: caloric restriction. So having less food for a portion of
Speaker 2: your life increases lifespan in a lot of animal models.
Speaker 2: So there are a lot of different host factors that
Speaker 2: are implicated as a possibility in this. Some of them
Speaker 2: are things you've definitely heard of, like insulin right or
Speaker 2: IGF one insulin growth factor one. There are a lot
Speaker 2: of others like m tour amp K sirtuins are in
Speaker 2: amp K. These are all various fancy names for factors
Speaker 2: that our body uses to help signal to our brain
Speaker 2: when there is food that needs to be digested versus
Speaker 2: when our nutrients stash is very low, so we need
Speaker 2: to engage in catabolism like break down our own stores
Speaker 2: instead of building a bunch of muscle in fat. So
Speaker 2: there's evidence to suggest that states of anabolic signaling that
Speaker 2: is our body saying, hey, we've got a lot of food,
Speaker 2: we need to build up stores. That process accelerates aging,
Speaker 2: at least in mice and so manipulating this signaling so
Speaker 2: that a mouse's metabolism thinks it's living underlimited nutrients. By
Speaker 2: manipulating some of these factors can extend longevity.
Speaker 1: Interesting, So that's that's what is meant by caloric restriction,
Speaker 1: is manipulating the factors, not straight up chloric restriction.
Speaker 2: So straight up coloric restriction means straight up coloric restriction.
Speaker 1: Okay.
Speaker 2: This is trying to get out a way of can
Speaker 2: we trick our bodies into thinking that we're living colorically restricted,
Speaker 2: but we don't want to live calorically restricted?
Speaker 1: What is the mechanism for chloric restriction increasing longevity? And
Speaker 1: what does chloric restriction mean?
Speaker 2: Great questions. So caloric restriction in animal models means reducing
Speaker 2: an animal's nutrient intake to about thirty to forty percent
Speaker 2: of what is typically considered necessary for like, you know,
Speaker 2: the amount of calories that a mouse needs. So it's
Speaker 2: very very restricted. I want to be extremely clear on
Speaker 2: here that I am not by any means recommending this
Speaker 2: for human beings. This could be very dangerous, okay, but
Speaker 2: in mice, restricting them to that very small amount of
Speaker 2: calories thirty to forty percent of what would normally be needed,
Speaker 2: does increase lifespan, and it also increases the age at
Speaker 2: which animals are able to reproduce, if that makes sense.
Speaker 1: It increases how long you are reproductively viable.
Speaker 2: Well, no, because these animals tend to not be able
Speaker 2: to reproduce while they're living under caloric restriction. But then
Speaker 2: they get to an age where normally, like a normal
Speaker 2: mouse at say this many months of life would no
Speaker 2: longer be able to reproduce. This mouse who's been calorically
Speaker 2: restricted now can reproduce if you start feeding them.
Speaker 1: Okay, butzing if the mouse is only consuming thirty to
Speaker 1: forty percent of what is considered neces necessary for it
Speaker 1: to live, how is it living well?
Speaker 2: So that is the idea behind all of these factors. Basically,
Speaker 2: the thought is that in so doing, in restricting these calories,
Speaker 2: you're altering the way that the body is metabolizing everything
Speaker 2: in a way that is promoting catabolism. So that breaking
Speaker 2: down of our own body stores rather than anabolism, the
Speaker 2: building up of our muscles, the building up.
Speaker 1: Of fat stores. Right.
Speaker 2: So that's the idea behind why caloric restriction works. We
Speaker 2: know from animal model studies from a long long time
Speaker 2: ago that restricting animals diets makes them live a longer time.
Speaker 2: These genes and these factors and these hormones that have
Speaker 2: been identified seem to be the possible mechanistic way that
Speaker 2: caloric restriction manifests. So if we could directly affect those
Speaker 2: mTOR or insulin or what have you, so then we
Speaker 2: could trick our bodies into breaking down stores rather than
Speaker 2: building fat, and that might make us live longer. That's
Speaker 2: the theoretical idea behind it.
Speaker 1: Interesting. Yeah, it kind of it reminds me of going
Speaker 1: back to the evolutionary hypotheses, the germ soma theory, where
Speaker 1: it's like the germ line is always favored, but maybe
Speaker 1: here's the exception where if the soma line can't support
Speaker 1: the germ line, then the soma line has to be favored. Yes, first, exactly.
Speaker 2: I think that that is a good way to kind
Speaker 2: of yeah, pieces together.
Speaker 1: Interesting.
Speaker 2: Okay, there's a few more, but I will say I'm
Speaker 2: not going to go into quite as much detail because
Speaker 2: from what I read, the topics that I've already covered
Speaker 2: are maybe the ones where we are a little bit
Speaker 2: farther along in that we have data from animal models
Speaker 2: and from cell models to show that manipulating these various things,
Speaker 2: be they nutrient sensing or you know, protein stability can
Speaker 2: affect aging. The other ones are a bit more theoretical still,
Speaker 2: at least from what I read. And apologies. If someone
Speaker 2: has some great data that I didn't see on these
Speaker 2: last few.
Speaker 1: Topics, send it our way, ye if you do, I.
Speaker 2: Would love to read it. So another possibility is the
Speaker 2: idea of mitochondrial dysfunction. So our mitochondria are often called
Speaker 2: the powerhouse of our cells. They do a lot for
Speaker 2: our bodies, and the idea is that over time, just
Speaker 2: like our DNA in our nucleus, these mitochondria can just
Speaker 2: sort of not function as well anymore. This is thought
Speaker 2: to be very related to things like oxidative stress over time.
Speaker 2: That's all I got for you on mitochondrial dysfunction related
Speaker 2: likely to the process of aging. Okay, there's also just
Speaker 2: the idea of cellular sinescence in general, cells going quiescent
Speaker 2: over time. A lot of our cells in our body
Speaker 2: are not dead, but they no longer divide, they're no
Speaker 2: longer active. So there's a large thought that just this
Speaker 2: entire process of cells kind of turning off a lot
Speaker 2: of their activity then relates to aging, and it's likely
Speaker 2: protective to write, like, reduce the amount of DNA damage
Speaker 2: that might occur through the process of replicating cells that
Speaker 2: don't need to be replicated, et cetera. So this might
Speaker 2: be something that's more related to protection against aging rather
Speaker 2: than involved in the process of aging, like protective against it.
Speaker 1: Yeah, yeah, Okay.
Speaker 2: Then there's the idea of stem cell exhaustion, which I
Speaker 2: again didn't get that much into detail of, but the
Speaker 2: idea that our stem cells are the ones that aren't
Speaker 2: able to keep up the way that they need to
Speaker 2: to be able to produce more cells correctly, like the
Speaker 2: basal layer of our skin. Cells are stem cells that
Speaker 2: can become any various type of cell. But as insults
Speaker 2: occur to these stem cells, then hence the process of
Speaker 2: aging AI yeah.
Speaker 1: Yeah.
Speaker 2: And finally, there is also this thought of defective or
Speaker 2: diminished cell to cell communication. And there's a lot that
Speaker 2: probably goes into this one that I think is interesting
Speaker 2: and I didn't I will full disclosure, actually read any
Speaker 2: papers by him, but I watched a TED talk of
Speaker 2: this researcher named Michael Levin, who is a researcher at
Speaker 2: Tufts University and does really interesting research on cell cell
Speaker 2: communication from a bioelectric field perspective. Right, it's very very interesting.
Speaker 2: But there's also a lot of other ways that our
Speaker 2: cells communicate with each other besides potentially a bioelectric field.
Speaker 2: But I will link to that Ted talk because it's
Speaker 2: fascinating and it's likely that this process over time also
Speaker 2: becomes defective and is involved in the process of aging.
Speaker 2: That was like a very fast speed through and I
Speaker 2: know that I left a lot of detail out. I
Speaker 2: will cite a couple of papers, one from twenty thirteen
Speaker 2: that's a few years old now, but another that is
Speaker 2: a summary of a twenty twenty one symposium of gerontologists
Speaker 2: that has a lot more detail on these nine different
Speaker 2: processes and where we kind of stand in terms of
Speaker 2: in vitro cell data, animal model data, and human data.
Speaker 2: But the thing is, I think it's very clear just
Speaker 2: for going over all those various processes that these are
Speaker 2: all very interconnected, right, especially when we talk about humans.
Speaker 2: It's not one single piece. All of these processes are
Speaker 2: likely at play, and we are not at a point
Speaker 2: where we can say that we have an answer or
Speaker 2: a drug or an intervention at all. That can prolong
Speaker 2: our life in any meaningful way. We don't even have
Speaker 2: one that could likely prolong our health, at least not yet.
Speaker 2: So really, for me, what it comes down to is
Speaker 2: that forever it is a very very long time. So
Speaker 2: do I think it's possible that humans will ever unlock
Speaker 2: the many locks between us and immortality? No, I will say, no, Yeah,
Speaker 2: it doesn't seem likely. It doesn't. Do I think that
Speaker 2: it could be theoretically possible this concept of immortality kind
Speaker 2: I kind of don't, Aron, do you know?
Speaker 1: No, But I will say that Also what occurred to
Speaker 1: me while you know, listening to you and while thinking
Speaker 1: about the part that I went through, is that maybe,
Speaker 1: you know, this is one of those things where in
Speaker 1: the future, in the distant future, if anyone ever stumbles
Speaker 1: across this podcast and they'll just laugh, I know how
Speaker 1: naive we were and how unbelieving we were.
Speaker 2: Yeah, I maybe maybe I similarly doubt it.
Speaker 1: I mean, and I think that's the other thing too,
Speaker 1: is that immortality is not what people are working on exactly,
Speaker 1: it's how it's being sold.
Speaker 2: Yes, And one of the things that I think is
Speaker 2: really interesting in reading from the gerontology perspective is that
Speaker 2: I do think that a lot of the research into
Speaker 2: these questions of like how does aging happen and can
Speaker 2: we manipulate those processes? This research can be used to
Speaker 2: improve the lives of humans, and I do think that
Speaker 2: it could potentially increase our health span and delay the
Speaker 2: onset of all these various aging related diseases. But what's
Speaker 2: interesting is that we tend to study all of these
Speaker 2: various age related diseases, cardiovascular disease, cancer, Alzheimer's disease. We
Speaker 2: study these diseases in isolation.
Speaker 1: Ooh, that's such a good point.
Speaker 2: And aging itself is not considered a disease, so you
Speaker 2: cannot study it from a like applying for nih Grant's perspective,
Speaker 2: or from a drug development perspective. You cannot study it
Speaker 2: in the same way that you can study diseases.
Speaker 1: Oh, that is very interesting.
Speaker 2: It really is, because it also means that the funding
Speaker 2: is not actually being directed towards aging. The funding from
Speaker 2: the government is being directed towards addressing these diseases that
Speaker 2: we think maybe could be preventable. Right, But if we
Speaker 2: think that these are inter related diseases that are all
Speaker 2: part of the process of aging, then wouldn't it make
Speaker 2: more sense to address them from a wider perspective by
Speaker 2: addressing these underlying mechanisms rather than addressing cardiovascular disease or
Speaker 2: diabetes itself and cancer itself. Let's think about these things
Speaker 2: that underpin both of those or all of those. And
Speaker 2: so I think that that's kind of the argument of
Speaker 2: a lot of the people who do this type of research,
Speaker 2: and I think it's really valid. And maybe that's the
Speaker 2: gap that some of these biotech companies are filling by
Speaker 2: directing their funding to address that. I don't know, maybe
Speaker 2: that's an optimistic view, but maybe that is.
Speaker 1: That's a really good point. And I mean, I know
Speaker 1: that like a lot of epidemiological studies will look at
Speaker 1: all of these things together, but it just there are
Speaker 1: so many different avetus of research.
Speaker 2: Yeah, and but it.
Speaker 1: Does seem like aging is super multifactorial. A lot of
Speaker 1: these diseases are super multifactorial, but some of the factor
Speaker 1: like that they are like siloed diseases exactly. That's yeah.
Speaker 2: I also think it's important to point out, like you mentioned, Aaron,
Speaker 2: there are a lot of other in my mind, ethical
Speaker 2: and moral concerns related to this idea of pursuing an
Speaker 2: increased lifespan or health span in thinking about the state
Speaker 2: of our planet and climate change and how we've impacted
Speaker 2: our planet with the lifespans that we currently have, and
Speaker 2: also in like you said, where is this development and
Speaker 2: technology going to go? Who is going to benefit from it?
Speaker 2: Because the increase in life span that we've seen in
Speaker 2: the last fifty to one hundred years hasn't been even
Speaker 2: across the board, and people who are wealthy live much
Speaker 2: longer than people who are not wealthy, and so that
Speaker 2: is likely going to continue to be true, especially if
Speaker 2: all of the research being done on this is from
Speaker 2: a capitalistic perspective of companies trying to make money off
Speaker 2: of it.
Speaker 1: I don't know. I mean, anti aging is one of
Speaker 1: the world's biggest industries.
Speaker 2: Yeah, definitely, it really is.
Speaker 1: And like, and I'll repeat again, not a single anti
Speaker 1: aging product has been shown to actually slow stop or
Speaker 1: reverse aging in any capacity.
Speaker 2: Yeah, diet and exercise, erin diet and exercise. Yeah, listeners,
Speaker 2: do you think you'd want to live forever? I'm curious.
Speaker 1: I'm curious, and if so.
Speaker 2: Why or why not?
Speaker 1: Or why not?
Speaker 2: Yeah?
Speaker 1: Should we do sources? Yeah? I have a bunch, but
Speaker 1: I'm going to shout out two books in particular that
Speaker 1: I found really helpful. So in terms of the evolution
Speaker 1: of sinessence and the evolution of aging. There is a
Speaker 1: book by Jefferson at All or a bunch of editors
Speaker 1: titled The Evolution of Sinessence in the Tree of Life,
Speaker 1: and that's from twenty seventeen. And then the book that
Speaker 1: I already mentioned by Stephen Cave Immortality the Quest to
Speaker 1: Live Forever and how it drives Civilization, and those are
Speaker 1: both really I just really enjoyed the Stephen Cave book
Speaker 1: as an interesting way to look at immortality.
Speaker 2: I had a couple that I enjoyed. Those two that
Speaker 2: focused on the various hows of aging were a paper
Speaker 2: from Cell in twenty thirteen titled the Hallmarks of Aging,
Speaker 2: as well as a symposium report from the Annals of
Speaker 2: the New York Academy of Sciences from twenty twenty two
Speaker 2: titled Extending Human Lifespan and Longevity a symposium report. I
Speaker 2: also thought an important one to mention is a paper
Speaker 2: from twenty twenty one called Longevity Leap Mind the Health
Speaker 2: Span Gap. And then there was there's a bunch more
Speaker 2: so I'll link to them on our website, This podcast
Speaker 2: will kill You dot com under the episodes TAT.
Speaker 1: Thank you to Bloodmobile for providing the music for this
Speaker 1: episode and all of our episodes.
Speaker 2: Thank you to the Exactly Right Network, of whom we're
Speaker 2: proud to be a part.
Speaker 1: And thank you to you listeners. I really hoped that
Speaker 1: you liked this one.
Speaker 2: Yeah yeah, I hope so too. And a special thank
Speaker 2: you to our patrons as always, thank you so much
Speaker 2: for supporting us.
Speaker 1: Yeah well erin Happy one hundred, Happy one hundred and
Speaker 1: until next time, wash your hands.
Speaker 2: You filled the animals m